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UNIDENTIFIED ANNOUNCER: Listener-supported WNYC Studios.

[RADIOLAB INTRO]

JAD ABUMRAD: Hey. I'm Jad. This is RADIOLAB. So last week, we heard a story from Molly Webster. It was all about a new emerging disease. And this week, we're actually going to go back to Molly.

MOLLY WEBSTER: Well, hello.

JAD ABUMRAD: Hey. There you are.

MOLLY WEBSTER: Yay.

JAD ABUMRAD: High-five. Yeah.

MOLLY WEBSTER: Hi.

JAD ABUMRAD: Because she has some new information about a story that she did a while back about beating back a disease, a disease that's been around for a while.

MOLLY WEBSTER: So...

JAD ABUMRAD: We're talking about - well, sorry. You start.

MOLLY WEBSTER: No, we're talking about gamma, which is interesting because gamma was when you were gone.

JAD ABUMRAD: Yeah, I remember that.

MOLLY WEBSTER: It was during your sabbatical.

JAD ABUMRAD: So here's the deal. It was 2016. I had taken a little break from the show, just a few months. And Molly, along with Robert, decided to do something a little bit different on the show. She actually broke some news. She'd gotten a hot tip about some research that was just out from MIT. And it was about Alzheimer's.

MOLLY WEBSTER: And when I was there, they were in the midst of doing some really exciting follow-up research that they had told me about off the record, but they weren't ready to talk about. But now they are ready...

JAD ABUMRAD: Cool.

MOLLY WEBSTER: ...To talk about it.

JAD ABUMRAD: OK, so here's what we're going to do. We're going to play the original piece, and then current-day 2020 Molly and Jad will pop in along the way with some updates. But for now, here is 2016 Molly with 2016 Robert.

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ROBERT KRULWICH: Hi. I'm Robert Krulwich.

MOLLY WEBSTER: I'm Molly Webster.

ROBERT KRULWICH: This is RADIOLAB. And today...

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MOLLY WEBSTER: We've got breaking news, Robert Krulwich.

ROBERT KRULWICH: On - break - this is something we've never done before.

MOLLY WEBSTER: (Laughter) Never done before.

ROBERT KRULWICH: Well, does anybody know about this yet?

MOLLY WEBSTER: Well, it is a new bit of research. It's being published today. We've known about it for the last few months, but we haven't been able to talk about it until now.

ROBERT KRULWICH: What's this thing about?

MOLLY WEBSTER: Oh, this is a discovery about Alzheimer's disease, which I think at this point is something that affects basically every family.

ROBERT KRULWICH: Affected my family, yeah.

MOLLY WEBSTER: Yeah. And this is a discovery that is not a cure, but it's basically about looking at the brain, which is one of the most complicated things in the universe, I think.

ROBERT KRULWICH: Yeah.

MOLLY WEBSTER: ...And poking at it in this super simple way and getting this bizarre result.

ROBERT KRULWICH: How bizarre?

MOLLY WEBSTER: It's pretty, pretty bizarre.

ROBERT KRULWICH: (Laughter).

LI-HUEI TSAI: Hello?

MOLLY WEBSTER: Hello, hello.

LI-HUEI TSAI: Hi, Molly.

MOLLY WEBSTER: Hi.

LI-HUEI TSAI: Hi. How are you?

MOLLY WEBSTER: All right. So last May, I was talking to some folks over at the Brain Institute at MIT. And while I was on the phone with them, they started telling me about some research that hadn't been published yet. So it was all very hush-hush. It was pretty cool, though. We ended up deciding to sign a nondisclosure agreement. And it was based on the work of this woman, Li-Huei Tsai.

LI-HUEI TSAI: Li-Huei Tsai.

MOLLY WEBSTER: Tsai?

LI-HUEI TSAI: Tsai.

MOLLY WEBSTER: Tsai, OK.

LI-HUEI TSAI: Yeah. I'm a professor and the director of the Picower Institute for Learning and Memory at MIT.

MOLLY WEBSTER: Holy crap. You're the director. How do you have time to do all of that?

LI-HUEI TSAI: I know. That's a good question (laughter).

MOLLY WEBSTER: She is, like, a badass, is what she is.

ROBERT KRULWICH: (Laughter).

LI-HUEI TSAI: But this is the piece of work I'm very proud of and very excited about (laughter). So...

MOLLY WEBSTER: OK, cool. So, I mean, you...

LI-HUEI TSAI: So let me begin.

MOLLY WEBSTER: OK.

LI-HUEI TSAI: So, historically, people work on Alzheimer's really focus a lot on...

MOLLY WEBSTER: So I would say, generally, when you talk to researchers about Alzheimer's disease, they either focus on...

LI-HUEI TSAI: ...On individual genetic factors.

MOLLY WEBSTER: ...The genetics of the disease, so the genes that predispose you, maybe, to Alzheimer's.

LI-HUEI TSAI: Or...

MOLLY WEBSTER: The brain chemistry and how Alzheimer's affects the chemicals in the brain.

LI-HUEI TSAI: ...Molecular pathological features.

MOLLY WEBSTER: But in my conversation with Li-Huei, she was talking about something totally different.

LI-HUEI TSAI: We sort of look at it from a different angle.

MOLLY WEBSTER: Her work all centers around something called...

LI-HUEI TSAI: The gamma frequency.

ROBERT KRULWICH: The gamma frequency?

MOLLY WEBSTER: Mmm hmm.

LI-HUEI TSAI: Gamma.

MOLLY WEBSTER: And what is - I'm like, it feels like something from "Battlestar Galactica."

(LAUGHTER)

MOLLY WEBSTER: So I don't think it's that.

LI-HUEI TSAI: So this gamma, so-called gamma...

MOLLY WEBSTER: You could think of it as a particular beat...

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MOLLY WEBSTER: ...In your brain.

ROBERT KRULWICH: A beat in the brain.

MOLLY WEBSTER: Yeah.

LI-HUEI TSAI: Yeah.

ROBERT KRULWICH: Which means what exactly?

MOLLY WEBSTER: Well, just to oversimplify one of the most complicated things in the known universe...

ROBERT KRULWICH: OK (laughter). Please do.

MOLLY WEBSTER: You've got your brain. It's full of neurons, which are a certain type of brain cell.

LI-HUEI TSAI: We have billions of neurons in the brain.

MOLLY WEBSTER: They have these long tentacles that are reaching out towards other neurons.

LI-HUEI TSAI: And for the brain to function, neurons have to communicate with each other to process information.

MOLLY WEBSTER: And the way they do that is they fire.

LI-HUEI TSAI: Yes.

MOLLY WEBSTER: An electrical signal will go through them, and it'll, like, zap another neuron, and it'll turn it on, and then it'll - like, an electrical signal will go through it, and it'll zap another neuron, and it'll turn it on. But the cool thing is, is that when your brain is doing things like making you move or write a poem or think great thoughts, groups of neurons...

LI-HUEI TSAI: Fire in sync.

MOLLY WEBSTER: All together on the same...

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MOLLY WEBSTER: ...Beat. And there's a bunch of different beats that happen in the brain. Some of them are slow, like one beat per second, and that's when you're sleeping. If you're beating around 10 beats per second, like maybe you're sitting next to a campfire in an Adirondack chair. Or on, like, the totally other end of the spectrum, like, some neurons fire at 600 beats per second.

ROBERT KRULWICH: What are they doing?

MOLLY WEBSTER: That I have no idea. I just...

ROBERT KRULWICH: And all this is going on in your head simultaneously?

MOLLY WEBSTER: Yeah, yeah. No, that's the cool thing - is that when all of these beats in your brain come together, that's when you're able to process the world and understand it as it exists, as human beings.

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ROBERT KRULWICH: Huh.

MOLLY WEBSTER: But getting back to our story, when your brain is doing something really tricky that requires super focused...

LI-HUEI TSAI: Attention, working memory and so on.

MOLLY WEBSTER: You're, like, trying to find your way home from the subway station or if you're in a new city, you know, navigate around it, there's a certain beat that sort of rises above them all and that is...

LI-HUEI TSAI: The so-called gamma frequency.

MOLLY WEBSTER: This range between 30 beats per second all the way up to 100 beats per second.

LI-HUEI TSAI: And this gamma frequency has been considered to be very important for the higher order cognitive function.

MOLLY WEBSTER: And the interesting thing is that when you look at an Alzheimer's brain, what you see is there's actually less gamma happening or people say like the power of gamma is reduced.

LI-HUEI TSAI: Not all the neurons can be recruited to oscillate at the gamma frequency.

MOLLY WEBSTER: It's still there. It's just quieter. It's like you turn the volume down.

LI-HUEI TSAI: Right.

ROBERT KRULWICH: All right. So just to briefly sum up here, what we've got is a rhythm which we call gamma which is used when we have complicated or higher thoughts in the brain, which, when you've got Alzheimer's, kind of gets saggy or tired.

MOLLY WEBSTER: Yeah. Yeah, totally. And, of course, obviously, in an Alzheimer's brain, there's a lot going on, and this is just one of the things, right? You've got the plaques that build up around the neurons.

ROBERT KRULWICH: The stuff that gucks up your brain and makes it hard to think.

MOLLY WEBSTER: Yeah, yeah, yeah, totally. It's like cobwebs in the brain. And then the connections between neurons gets all muddied, and immune cells get messed up. Li-Huei Tsai was like, forget all that. What would happen if I just bring the gamma back?

LI-HUEI TSAI: Yeah. We decided to just manipulate gamma oscillations.

ROBERT KRULWICH: And how do you do that?

MOLLY WEBSTER: Well...

Hello, hello, hello, hello, hello, hello, hello, hello.

Technology.

Hi, this is Molly, hi, hi, hi.

Technology you can find at the Massachusetts Institute of Technology. And actually, I went and took a train up to Boston to MIT not too long ago.

We're walking into the Picower Institute. It's a...

Wow.

…Big, shiny glass building.

LI-HUEI TSAI: Molly, hi, nice to meet you.

MOLLY WEBSTER: Eventually, Li-Huei Tsai came striding into her office to meet me.

LI-HUEI TSAI: My understanding is that you want to see some of the experimental setup.

MOLLY WEBSTER: And so Li-Huei led me down the hall to this tiny room...

The mice just entered the room.

...Brought in these adorable little mice.

Oh, my gosh. They're like - little black and soft and furry. Their ears are tagged with a little metal tag on them.

LI-HUEI TSAI: OK. So...

MOLLY WEBSTER: So here's what they did. They get some mice.

LI-HUEI TSAI: We started off with a mouse model.

MOLLY WEBSTER: Not the mice I actually got all excited over but mice that have an early stage of Alzheimer's disease.

LI-HUEI TSAI: With multiple notable defects.

ROBERT KRULWICH: Do they have the gunky plaque stuff in them yet or is that later?

MOLLY WEBSTER: No, but they do have...

LI-HUEI TSAI: Elevated levels of beta amyloid peptides.

MOLLY WEBSTER: Which is this protein that forms the plaques. So it's like basically pre-plaque gunk. But the important thing to Li-Huei Tsai and her team is that they have less gamma going on in their brains. If you remember, the whole plan here is to bring the gamma back.

LI-HUEI TSAI: Yes.

MOLLY WEBSTER: So to do that, they get what might be the world's tiniest drill, and they drill a small hole into the skull of the mouse. And then they take a really thin fiber-optic cable, they slide it through the hole into the brain. And then they get this laser of blue light...

LI-HUEI TSAI: To flicker.

MOLLY WEBSTER: At 40 beats per second.

LI-HUEI TSAI: Gamma frequency.

MOLLY WEBSTER: And they turn that on and the light travels down the fiber-optic cable deep down into the brain to this group of cells that they've modified...

LI-HUEI TSAI: In the hippocampus.

MOLLY WEBSTER: ...To be sensitive to light. So when this pulsing light hit these cells, they actually began to fire at 40 beats per second.

LI-HUEI TSAI: At gamma frequency.

MOLLY WEBSTER: And they would keep these cells firing at gamma.

LI-HUEI TSAI: For one hour.

MOLLY WEBSTER: Firing and firing and firing and firing and firing.

LI-HUEI TSAI: And then after one hour...

MOLLY WEBSTER: They turn off the light and then eventually they started looking at the brains of these mice trying to figure out if anything was different after the light flashed. And they see...

LI-HUEI TSAI: To our much surprise...

MOLLY WEBSTER: We're not expecting this at all.

LI-HUEI TSAI: ...We found...

MOLLY WEBSTER: After they shot this pulsing light into the brain, there was suddenly nearly half as much of that soon-to-be-nasty plaque gunk stuff that was filling up their hippocampus.

ROBERT KRULWICH: A half of the...

MOLLY WEBSTER: Yeah.

ROBERT KRULWICH: Half?

MOLLY WEBSTER: Half of the stuff was just swept away.

LI-HUEI TSAI: Yes - 40% to 50% reduction of beta amyloid.

MOLLY WEBSTER: That just seems crazy.

LI-HUEI TSAI: This is crazy. I mean, we were just so surprised.

ROBERT KRULWICH: Do they know why the flood of light would...

MOLLY WEBSTER: Yeah, yeah. So...

LI-HUEI TSAI: Turn out...

MOLLY WEBSTER: ...The pulsing light somehow triggered the brain's cleanup crew.

LI-HUEI TSAI: Microglia.

MOLLY WEBSTER: These cells in the brain that are called microglia.

LI-HUEI TSAI: You can say they're the janitors of the brain.

MOLLY WEBSTER: And in a normal brain, these janitor cells usually gobble up the gunk.

LI-HUEI TSAI: But in Alzheimer's disease, it's known that microglia, they don't sort of function normally anymore.

MOLLY WEBSTER: It's like these janitors just sort of...

LI-HUEI TSAI: Stop cleaning up.

MOLLY WEBSTER: And go on strike.

ANTHONY MARTORELL: There we go. OK. Cool.

MOLLY WEBSTER: OK. So we're looking at a screen that's now flat. It's not...

When I was at MIT, one of Li-Huei's grad students...

ANTHONY MARTORELL: My name is Anthony Martorell, second year.

MOLLY WEBSTER: ...Was showing me side-by-side comparisons of these mice brains on a screen.

ANTHONY MARTORELL: Can you guess what that is?

MOLLY WEBSTER: Which part?

ANTHONY MARTORELL: The green things.

MOLLY WEBSTER: Microglia.

ANTHONY MARTORELL: Microglia, yeah.

(LAUGHTER)

MOLLY WEBSTER: And you see...

LI-HUEI TSAI: After one hour of gamma...

MOLLY WEBSTER: Wow, so that...

LI-HUEI TSAI: ...The microglia, the cell, seems a lot bigger.

MOLLY WEBSTER: Clearly see these round bodies.

LI-HUEI TSAI: Yeah.

MOLLY WEBSTER: Yeah.

LI-HUEI TSAI: And also their belly (ph) seems to have more amyloid.

MOLLY WEBSTER: Oh, like they're doing more eating.

LI-HUEI TSAI: Yes. They go back to eat more amyloid again.

MOLLY WEBSTER: It's like somehow making the neurons fire turned on the sanitation system in the brain.

LI-HUEI TSAI: But - but the most wild results...

MOLLY WEBSTER: Wait. There's more wild?

LI-HUEI TSAI: Oh, my God. You got to hear this.

MOLLY WEBSTER: (Laughter) OK, OK.

LI-HUEI TSAI: ...Because what I'm about to tell you, you may say, no, I don't believe it; it's science fiction. OK.

MOLLY WEBSTER: So one of the things Li-Huei and her team were starting to think was that drilling and fiber-optic cable...

LI-HUEI TSAI: Is very invasive, right?

MOLLY WEBSTER: You'd never be able to do that on a human.

LI-HUEI TSAI: Exactly. So we started to say...

MOLLY WEBSTER: Well, what if we can get the light into the brain in a different way? Like, maybe we could go through the eyes.

ROBERT KRULWICH: So then the hole in your head would be your eyes instead of a hole in your head?

MOLLY WEBSTER: Yes.

LI-HUEI TSAI: Yes.

MOLLY WEBSTER: So Li-Huei and her team created what I like to think of as the flicker room.

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MOLLY WEBSTER: Wait. Is this the room?

LI-HUEI TSAI: This is the room.

MOLLY WEBSTER: (Laughter) OK.

It turns out, I learned upon my visit, it is just a storage closet.

You know, you have - what is this? Just, like, a plastic table.

Very DIY.

ANTHONY MARTORELL: Yeah, it's a plastic table you can buy at Target.

MOLLY WEBSTER: There were some plastic shoebox-sized containers lined up on the table for the mice. And then...

LI-HUEI TSAI: Do you see this strip?

MOLLY WEBSTER: Around the edge of the table...

LI-HUEI TSAI: Basically, surrounding all the cages.

MOLLY WEBSTER: ...Are duct-taped strips of LED lights.

ANTHONY MARTORELL: And the reason why we use LEDs is because a regular light bulb, it can't flash fast enough.

MOLLY WEBSTER: And so the idea is, what if we just put the mice in this room and just let the light flicker at 40 beats per second?

LI-HUEI TSAI: So you want to show Molly, like - turn this on?

MOLLY WEBSTER: Yeah.

And so we turn off the overhead light in the room so it's very black. And then...

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MOLLY WEBSTER: Oh, wow.

The room was now glowing with this white LED light.

ANTHONY MARTORELL: OK, so the light is turning on and off 40 times a second.

MOLLY WEBSTER: It's - so there's - you don't see anything going, like, on or off. It just looks like something's on.

LI-HUEI TSAI: Exactly.

MOLLY WEBSTER: But it kind of feels like my eye is twitching.

LI-HUEI TSAI: Exactly.

MOLLY WEBSTER: And so it's blurring the light a little, just on the edges, though.

LI-HUEI TSAI: Right. Right. Yeah, just on the edges.

MOLLY WEBSTER: And so they put mice in this room for an hour and just let them kind of bathe in this glow.

LI-HUEI TSAI: And guess what?

MOLLY WEBSTER: What?

LI-HUEI TSAI: We look at the amyloid beta levels in the ventral cortex, and we found there is a 50% reduction.

MOLLY WEBSTER: Fifty percent?

LI-HUEI TSAI: Fifty-percent reduction.

MOLLY WEBSTER: Just from shining light in their eyeballs?

LI-HUEI TSAI: Yes.

ROBERT KRULWICH: Wait a second. They didn't do any drilling in their skulls or anything?

MOLLY WEBSTER: No. No, they didn't drill. They didn't tweak the mouse's brain cells to be sensitive to light. This is just...

ROBERT KRULWICH: They just filled the room with occasional LEDs flashing at a particular frequency?

MOLLY WEBSTER: For an hour.

LI-HUEI TSAI: Now do you see? (Laughter) Are you going to doubt me? I don't believe it? It's science fiction?

(LAUGHTER)

MOLLY WEBSTER: And they followed this study up with another study which was done in the same way - sort of the same flicker room, light through the eyeballs, and only this time, they put the mice in there for one hour a day for seven days, and they took mice that had full-blown Alzheimer's. So this is, like, cognitive decline, they're forgetting things, and they've got hardened plaques in their brain. And they see the same thing - nearly half of the stuff was cleared away.

ROBERT KRULWICH: Wow.

MOLLY WEBSTER: Half.

ROBERT KRULWICH: Wow.

LI-HUEI TSAI: It's just flickering light in front of the mice.

MOLLY WEBSTER: That's the shock. I mean, that's the shocking thing. The thing I didn't understand after talking to you about your study was I was like, why hasn't everyone done this before? Like, why didn't everyone go, we should just shine lights through eyes?

LI-HUEI TSAI: See - well, you know, that's really the most unexpected and exciting aspect of our study, which is something this simple, yet, you know, it has never been done before, you know? That...

MOLLY WEBSTER: One of the things, one of the caveats here, is that if you don't do the flicker-light room every 24 hours, the level of gunk in the brain starts going back up again. And so now they're trying to figure out how they can keep those levels down, maybe even for good.

JAD ABUMRAD: OK, current-day Jad here. We'll come back to the original story in a bit and to a big question that all of this work raises. But, first, a little update - 2020 Molly recently called Li-Huei Tsai again...

MOLLY WEBSTER: Hello. Hello?

LI-HUEI TSAI: Hello, Molly.

MOLLY WEBSTER: Yay.

JAD ABUMRAD: ...To see what she has been up to since that original research.

MOLLY WEBSTER: How are you?

LI-HUEI TSAI: I'm doing great.

MOLLY WEBSTER: Yeah?

LI-HUEI TSAI: So much - new things coming up. And I'm just excited all the time.

MOLLY WEBSTER: (Laughter).

And so as I said when I was there in 2016, we had talked a bit off the record. And since then, Li-Huei Tsai has published papers, gone on the record. And what we were talking about is that they were looking to expand their sensory toolkit. So instead of using gamma light, they did...

LI-HUEI TSAI: Gamma sound.

MOLLY WEBSTER: What made you pick sound?

LI-HUEI TSAI: So we know that we can see, we can hear, we can taste, we can smell, we can touch. And among all of this, we figure that sound is relatively straightforward to produce a 40-hertz gamma sound.

JAD ABUMRAD: Oh, interesting. So instead of shining a light in the subject's eyes, they would play a tone or something, and it would have the same effect?

MOLLY WEBSTER: Yeah. So they just built a sound that has that same gamma frequency built into it, like the lights in the flicker room, and then they play it for the mice.

LI-HUEI TSAI: Yeah.

MOLLY WEBSTER: What is the equivalent of, like, the sound flicker room?

LI-HUEI TSAI: We basically just, you know, add, you know, loudspeakers.

MOLLY WEBSTER: So the sound comes in through the mouse ears.

LI-HUEI TSAI: Right. So there are sensory nerve cells.

MOLLY WEBSTER: Like the waves come in. It gets converted to an electrical signal.

LI-HUEI TSAI: This electrical signal then can be transmitted across the brain circuits.

JAD ABUMRAD: So wait. Do we know what it sounds like?

MOLLY WEBSTER: I have it here (laughter).

JAD ABUMRAD: Oh.

MOLLY WEBSTER: So I'm going to hit play, and then you tell me if you can hear it, OK?

JAD ABUMRAD: OK.

MOLLY WEBSTER: Oh, my God. It's kind of a crazy sound. I almost don't want to hit play (laughter). OK. 3, 2, 1.

(SOUNDBITE OF 40-HERTZ GAMMA SOUND)

JAD ABUMRAD: Oh, God.

MOLLY WEBSTER: Yeah.

JAD ABUMRAD: Whoa.

MOLLY WEBSTER: Yeah.

JAD ABUMRAD: It's like a little insect boring into my brain. And there's, like, a sub-bass in there that's making my stomach, like - ugh.

MOLLY WEBSTER: Right? I - the first time I heard it, I, like, ripped my headphones off my head. And then - I then really converted and found it super soothing.

JAD ABUMRAD: I'm not there yet (laughter).

MOLLY WEBSTER: I think we should probably also do the caveat of, like, there could be some way in which this comes through your headsets in a weird way. It depends on where the speaker is set, yada, yada, yada, where this is not the sound...

JAD ABUMRAD: Yes.

MOLLY WEBSTER: ...In a way that they are playing.

JAD ABUMRAD: And maybe we'd even want to take it a step further and say do not use this sound.

MOLLY WEBSTER: Yes. Please do not use this sound at home to self-treat. They were playing this for mice. Though when they were playing it for mice...

LI-HUEI TSAI: We were able to see very similar beneficial effects as those exposed to 40 hertz gamma light.

MOLLY WEBSTER: They see, like, the - what we talked about in the first episode, which were the microglia, which she calls, like, that the trash picker-uppers of the brain.

LI-HUEI TSAI: They just, you know, completely surround the amyloid plaques.

MOLLY WEBSTER: And so they start eating all that stuff up.

LI-HUEI TSAI: After one to two weeks of exposure, we saw about 30% to 40% reduction of the amyloid plaques.

JAD ABUMRAD: Wow. So listening to that sound that you just played - just listening to it is a kind of cleansing brain therapy of a kind?

MOLLY WEBSTER: I mean, yes, for mice right now, yes.

JAD ABUMRAD: Man.

MOLLY WEBSTER: The interesting thing is is they, as of yet, still have no idea why all this is happening. Why microglia seem to eat more of the trash, they have no idea.

JAD ABUMRAD: But they must have some theory - right? - or no?

MOLLY WEBSTER: No.

JAD ABUMRAD: No.

MOLLY WEBSTER: And she's done these studies at other rhythms, like...

LI-HUEI TSAI: Forty-one hertz or 42 hertz or 38 hertz or...

MOLLY WEBSTER: You know, they've tried 80 and they've tried 20. And for some reason, 40 is the sweet spot where you see this activity and you don't see it in other places. But beyond the why - like, why is it 40, or why does gamma do this and nothing else does this, or other things like gamma don't do this - all the new stuff with sound actually leads us to the same question we had in the original episode, the big question which Robert put to me.

(SOUNDBITE OF ARCHIVED BROADCAST)

ROBERT KRULWICH: If the mouse no longer has quite as much junk in its head, does that mean that it can remember things that had happened to it, it gets mentally more acute?

MOLLY WEBSTER: Yeah. That is their big next research. That's...

ROBERT KRULWICH: So they don't know.

MOLLY WEBSTER: They don't know. That's what they're to - that is now the next step. But nobody really understands how plaques and the gunk buildup in the brain relates to memory and cognition. And the dogma in the field is that when you have Alzheimer's, you can't form new memories. And once you lose a memory, it's gone for good. But there is another group at MIT that is actually sort of challenging that assumption that you can never get a memory back.

DHEERAJ ROY: Because the patient could never tell us, we all assumed the information had to be gone.

ROBERT KRULWICH: Oh, really?

MOLLY WEBSTER: Yeah. And we'll get to them. But first, we have to go to a break.

ROBERT KRULWICH: (Laughter) OK.

(SOUNDBITE OF SONG, "SEXY BACK")

TIMBALAND: (Singing) Take it to the bridge.

JAD ABUMRAD: And, of course, we'll be back with more updates right after this.

(SOUNDBITE OF MUSIC)

JAD ABUMRAD: Hey, Jad here. We are back looking back at Molly Webster's piece from 2016, peppering in some updates as we go. We're going to keep rolling here with the original for a beat, and then we'll get more from current-day 2020 Molly and me in a little bit.

(SOUNDBITE OF ARCHIVED BROADCAST)

ROBERT KRULWICH: I'm Robert Krulwich.

MOLLY WEBSTER: I'm Molly Webster.

ROBERT KRULWICH: This is RADIOLAB.

MOLLY WEBSTER: And we're back.

ROBERT KRULWICH: And just before the break, you said that there may be a way to bring a memory back from the Alzheimer's disease, to pull the memory back into place.

MOLLY WEBSTER: Yeah.

DHEERAJ ROY: Why are we so quick to jump to the conclusion that the information was somehow completely gone?

MOLLY WEBSTER: And the person who said that to me is this guy.

DHEERAJ ROY: I'm Dheeraj Roy. I'm a fourth-year graduate student in the Susumu Tonegawa Lab.

MOLLY WEBSTER: Over at the Tonegawa Lab, they were thinking what if we could figure out exactly where the memory should be in the brain and just give that spot a little bit of juice?

DHEERAJ ROY: Right.

MOLLY WEBSTER: So they took some mice that were just starting to lose their ability to remember things and they thought, OK, let's try to give them a memory.

DHEERAJ ROY: We put them in a box that has a particular smell, some sort of lighting and some texture on their feet.

MOLLY WEBSTER: A little mouse carpet or (laughter)...

DHEERAJ ROY: That's exactly what it is.

MOLLY WEBSTER: Wait. Really?

DHEERAJ ROY: Yeah.

MOLLY WEBSTER: OK. Mice on carpets, got it.

The point is the box looks and feels and smells different than any other box they would hang out in.

DHEERAJ ROY: And then you give them a light electrical shock.

MOLLY WEBSTER: And the mice, they just freeze.

DHEERAJ ROY: They don't move at all.

MOLLY WEBSTER: Which is a sign that they're afraid.

DHEERAJ ROY: They hate the box.

MOLLY WEBSTER: And for the rest of the afternoon, which is a very long time in mouse time, they go on hating the box, which means with the carpet and the light and the smell, if you put it back in there, it'll freeze because it remembers the shock.

DHEERAJ ROY: Yes.

MOLLY WEBSTER: But...

DHEERAJ ROY: A day or a week later...

MOLLY WEBSTER: When these same mice were put back into the same box...

DHEERAJ ROY: Instead of being scared of the box, they would just continue investigating as if nothing happened. They could not remember.

MOLLY WEBSTER: So Dheeraj and his team did what Li-Huei did. They got some modified mice, and then they put a little hole in their head, they slid in a fiber-optic cable, they shined some light to trigger the neurons that they think hold this memory. And they were...

ROBERT KRULWICH: In the fear section.

MOLLY WEBSTER: Near the fear section. So leading on the path to the fear section.

DHEERAJ ROY: So we do this.

MOLLY WEBSTER: And then...

DHEERAJ ROY: Put them back into the box...

MOLLY WEBSTER: The box with the particular lighting and smell and carpet.

DHEERAJ ROY: ...And ask, is there any change in their behavior?

MOLLY WEBSTER: Will they act afraid again?

DHEERAJ ROY: Do they show any more memory? And they did.

MOLLY WEBSTER: Wait. Shut up. They actually were scared of the box again?

DHEERAJ ROY: Exactly. They showed recovered memory.

MOLLY WEBSTER: Wow.

ROBERT KRULWICH: Whoa.

(SOUNDBITE OF MUSIC)

MOLLY WEBSTER: So that's like, bam, that memory's in there.

DHEERAJ ROY: Exactly. Voila. The behavior is back.

ROBERT KRULWICH: And you can dig up the memory by shining light in the right place?

MOLLY WEBSTER: Yeah.

DHEERAJ ROY: Mmm hmm.

MOLLY WEBSTER: I was always under the impression that the memories were totally lost.

DHEERAJ ROY: Right. So I think that's not just you; I think that's essentially the entire field, what you described.

MOLLY WEBSTER: Oh, OK. (Laughter) Well, that's good.

DHEERAJ ROY: Just because the patient could never tell us, we all assumed the information had to be gone.

ROBERT KRULWICH: Huh.

MOLLY WEBSTER: So one of the things to say is that Dheeraj did tell me that, you know, all of the experiments they did are in mice that have early Alzheimer's. The thought is, though, is that once you get to the late stage of the disease, there's enough damage in the brain that you really wouldn't be able to get those memories back.

ROBERT KRULWICH: That might be right, that a memory lost is just lost. But, you know, when you have someone in your house and you live with this disease, day in and day out, the disease just goes its own way. And it can puzzle you or frighten you or suddenly declare something new that you didn't expect.

So, for example, my dad had it for about nine, 10 years. It was a slow act of disappearing that he did where, I mean, the last time my father came to was so far into the disease, he hadn't spoken for a year and a half. He was sitting at the table for the Passover Seder. And there's a song that you sing, and it goes, (singing) day - dayenu, day - dayenu, day - dayenu, dayenu, dayenu.

So it's just a chorus. And from out of nowhere, this being at the end of the table who I knew was my father, who hadn't spoken in a year and a half or two and had not spoken coherently for three, suddenly flew into the song and sang the song, full-throatedly, at the table, like the reappearance of some just last figment of himself. And it was both horrifying and extraordinary - both, you know.

(SOUNDBITE OF MUSIC)

DHEERAJ ROY: I mean, I think that's - the fact that maybe some information still persists, hopefully someday we could kind of - maybe there's something we could do. But yeah, this is all in my mind at the moment (laughter).

(SOUNDBITE OF MUSIC)

LI-HUEI TSAI: As long as we can figure out how to rebuild the pathway to retrieve the memory, then I think there is hope.

MOLLY WEBSTER: And then I want to jump in here with one more part of the sound update, which is that Li-Huei and her team in particular are thinking about it in regard to capturing memories because where this research probably gets even, like, more interesting is when you do the light flashing and that sound at the same time.

LI-HUEI TSAI: We eventually just decided, why don't we, you know, put these two together and see how the animals respond?

MOLLY WEBSTER: This is becoming, like, a mice spa.

(LAUGHTER)

MOLLY WEBSTER: And when they did that, they saw this gamma beat in the brain - but not just in the auditory cortex or the visual cortex.

LI-HUEI TSAI: Not just in one particular brain region now. We are seeing across different brain regions.

MOLLY WEBSTER: So the hippocampus got involved, and the prefrontal cortex got involved, and then there was the neocortex and maybe even the parietal lobes. So there was, like, activity, like, all across the brain.

JAD ABUMRAD: Is a little bit like a whole bunch of, like, clocks coming into sync?

MOLLY WEBSTER: Yeah. Yeah. Yeah. And imagine thinking it's only going to affect one clock, but it actually somehow pulls them all into synchrony. Again, they saw the microglia doing their cleanup thing all across the brain. But most cooly (ph), they also saw just, like, almost, like, a rebuilding of neuronal circuitry. So, like, the synapses between neurons seemed to improve.

LI-HUEI TSAI: Then, basically, this repaired the disrupted neural circuitry. And I think this, in turn, can lead to recovery of learning a memory.

MOLLY WEBSTER: And what she's been finding with mice is that it seems to. Basically, in a way, she's done something very similar to what Dheeraj has done but with her own light and sound technique, and the memories came back.

JAD ABUMRAD: That's so interesting.

LI-HUEI TSAI: And the mice show very impressive improvement to their cognitive ability.

MOLLY WEBSTER: So it's almost like two things happening, which is you're seeing physiological effects in the brain, and then you're seeing the layer on top of that, which is then the memories that live in the physiology are also having some impact.

LI-HUEI TSAI: Yes.

MOLLY WEBSTER: So with all this stuff – super new, you feel like it's caveat time. And for the caveat, I am going to throw back to the caveat we had in the original piece.

(SOUNDBITE OF ARCHIVED BROADCAST)

LI-HUEI TSAI: You know, I personally think the most important question is whether humans respond similarly.

MOLLY WEBSTER: I mean, keep in mind that both Dheeraj's study and Li-Huei Tsai's are in mice, not humans.

LI-HUEI TSAI: Right. So I...

MOLLY WEBSTER: And do you have a thought that, like, why - like, is there a reason that a human neuron might react differently than a mouse?

LI-HUEI TSAI: The thing is, I think especially, you know, in Alzheimer's field, I mean, people got burned a lot.

MOLLY WEBSTER: You know, there's like a 99.6% failure rate in moving something that seemed to work in mice to humans in Alzheimer's.

ROBERT KRULWICH: Ninety-nine point six?

MOLLY WEBSTER: Yeah, yeah. That was a study that came out in 2012.

ROBERT KRULWICH: That's a horrible number.

LI-HUEI TSAI: So I just got to be really conservative here.

MOLLY WEBSTER: I'll dial it back. I'll dial it back.

LI-HUEI TSAI: You know...

MOLLY WEBSTER: Yeah.

LI-HUEI TSAI: ...What we have in mice is just so exciting and so unexpected. It's so much fun. But, you know...

(SOUNDBITE OF ARCHIVED BROADCAST)

LI-HUEI TSAI: ...I'm going to keep my mind open when it comes to humans.

MOLLY WEBSTER: The plan is that we're going to find out because they're going straight to humans.

ROBERT KRULWICH: Oh, they're going to do human trials.

MOLLY WEBSTER: Well, they want to. So, yeah, I guess we'll see.

And so we have my final final update, which is that Li-Huei Tsai and her crew have, indeed, started human trials.

LI-HUEI TSAI: So we, indeed, managed to get an IRB approved for our first very small-scale study in early-stage Alzheimer's disease subjects.

MOLLY WEBSTER: They're doing a clinical trial with 15 Alzheimer's patients.

JAD ABUMRAD: How far into the study are they?

MOLLY WEBSTER: I talked to Li-Huei in January, and they had some people enrolled.

LI-HUEI TSAI: So we have recruited 15 individual people. We basically installed our light and sound device in their homes.

MOLLY WEBSTER: Really?

LI-HUEI TSAI: Yeah. So they themselves or their caregiver can turn on the device.

MOLLY WEBSTER: And then they sit there and they get the light flashed in their eyes, and they get the sound flashed at their ears. And they're doing it an hour a day for six to eight months, maybe six to nine months. And they're just collecting data. And I guess we're going to see.

LI-HUEI TSAI: You know, we are talking about living human beings.

MOLLY WEBSTER: (Laughter).

LI-HUEI TSAI: It's not that we can just take out the brain and see their microglia or, you know, all of this. But we are evaluating the - all of the subjects in terms of their cognitive ability. And we also do MRI scan to look at how active their brain activity is.

JAD ABUMRAD: And do you have any intel on what they're seeing so far?

MOLLY WEBSTER: Nada. I wish.

LI-HUEI TSAI: I mean, every step of the way, to be quite honest, it's always a surprise. It's, oh...

MOLLY WEBSTER: Yeah.

LI-HUEI TSAI: ...This can do - you know, gamma can do this and gamma can do that. You know, I think that the journey - it's like a magic carpet ride.

ROBERT KRULWICH: This is the glorious part of all this. This organ of ours, the brain, is so crazily complicated with, like, whatever - 100 trillion connections or whatever it is. There's so much chance, there's going to be a lot of surprise.

(SOUNDBITE OF ARCHIVED BROADCAST)

MOLLY WEBSTER: Yeah. It's like almost even if it doesn't lead to any treatment in humans or something super concrete, it's like we know this little secret about the brain now. And there's something that feels, like, beautiful in that.

(SOUNDBITE OF MUSIC)

LI-HUEI TSAI: Yeah, I'm actually setting this up for my Christmas tree.

MOLLY WEBSTER: Are you really?

LI-HUEI TSAI: Yes. Yeah, we - I just bought the new LED lights, and they can flicker a different color - with different colors.

MOLLY WEBSTER: Oh, so each individual bulb can travel through colors, but while they're doing that, they're going to be flickering at 40.

LI-HUEI TSAI: We're going to have a very therapeutic Christmas (laughter).

MOLLY WEBSTER: In the Li-Huei Tsai household? This is the tree in your home.

LI-HUEI TSAI: Yes, yes.

MOLLY WEBSTER: I want to have an eggnog next to that tree.

ROBERT KRULWICH: Yeah.

MOLLY WEBSTER: And this year...

(SOUNDBITE OF MUSIC)

MOLLY WEBSTER: ...Might even add some 40-gamma jingle bells. Who knows?

(SOUNDBITE OF MUSIC)

JAD ABUMRAD: Wow. So cool.

MOLLY WEBSTER: And that's the update.

JAD ABUMRAD: Yeah. Thank you. Thank you, Molly.

(SOUNDBITE OF MUSIC)

JAD ABUMRAD: Obviously, this update was reported by Molly Webster, and it was produced by Rachael Cusick. And, of course, don't say this enough, big props to Soren Wheeler. Special thanks to Dheeraj Roy. I am Jad Abumrad, just a man who longs for the 40-kilohertz calming hum of the gamma. I shall go and listen to that sound now. In the meantime, thank you for listening. See you next week.

(SOUNDBITE OF MUSIC)

UNIDENTIFIED MUSICAL ARTIST: (Singing, unintelligible).

VERITY: Hi. This is Verity (ph) calling from Bristol in the U.K. RADIOLAB is created by Jad Abumrad with Robert Krulwich and produced by Soren Wheeler. Dylan Keefe is our director of sound design. Suzie Lechtenberg is our executive producer. Our staff includes Simon Adler, Jeremy Bloom, Becca Bressler, Rachael Cusick, David Gebel, Bethel Habte, Tracie Hunte, Matt Kielty, Tobin Low, Annie McEwen, Latif Nasser, Sarah Qari, Arianne Wack, Pat Walters and Molly Webster, with help from Shima Oliaee, Sarah Sandbach and Russell Gragg. Our fact-checker is Michelle Harris.

(SOUNDBITE OF MUSIC)

UNIDENTIFIED MUSICAL ARTIST: (Singing, unintelligible).

 

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